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Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome

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Glaze, Daniel G., Neul, Jeffrey L., Kaufmann, Walter E., Berry-Kravis, Elizabeth, Condon, Sean, Stoms, George, Oosterholt, Sean, Della Pasqua, Oscar, Glass, Larry, Jones, Nancy E., Percy, Alan K., Rett 002 Study Group, Glaze, Daniel G., Neul, Jeffrey L., Kaufmann, Walter E., Berry-Kravis, Elizabeth, Condon, Sean, Stoms, George, Oosterholt, Sean, Pasqua, Oscar Della, Glass, Larry, Jones, Nancy E., Percy, Alan·2019·Neurology
DOI 10.1212/wnl.0000000000007316PMC PMC6550498
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Abstract

OBJECTIVE: To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available. METHODS: This was a phase 2, multicenter, double-blind, placebo-controlled, parallel-group study, in which safety/tolerability, pharmacokinetics, and clinical response to trofinetide were characterized in 82 children/adolescents with RTT, aged 5 to 15 years. Sixty-two participants were randomized 1:1:1:1 to receive placebo twice a day (bid) for 14 days, followed by placebo, 50, 100, or 200 mg/kg bid of trofinetide for 42 days. Following blinded safety data review, 20 additional participants were randomized 1:1 to the 200 mg/kg or placebo bid groups. Safety assessments included adverse events, clinical laboratory tests, physical examinations, and concomitant medications. Clinician- and caregiver-based efficacy measurements assessed clinically relevant, phenotypic dimensions of impairment of RTT. RESULTS: All dose levels were well tolerated and generally safe. Trofinetide at 200 mg/kg bid showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behaviour Questionnaire, RTT-Clinician Domain Specific Concerns-Visual Analog Scale, and Clinical Global Impression Scale-Improvement. Exploratory analyses suggested that observed changes correlated with trofinetide exposure. CONCLUSION: These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children/adolescents with RTT, trofinetide was safe, well-tolerated, and demonstrated improvement over placebo at 200 mg/kg bid in functionally important dimensions of RTT.

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Crossref · 10.1212/wnl.0000000000007316

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Figure 1 Study design (A) and participant disposition (B) BID = twice daily dosing; ITT = intention to treat; mITT = modified intention to treat; PK = pharmacokinetic.
Figure 1 Study design (A) and participant disposition (B) BID = twice daily dosing; ITT = intention to treat; mITT = modified intention to treat; PK = pharmacokinetic.CC BY-NC-ND · PubMed Central
Figure 2 Core efficacy measures demonstrating improvement in the 200 mg/kg group compared to placebo (A) Change from treatment baseline of the 200 mg/kg group compared to placebo in the mITT population for the RSBQ total score. EOT measured at day 54. Posttreatment follow-up at day 66. Improvement is a decrease in score. LSmeans: placebo response included as covariate in the model. (B) Absolute values of the 200 mg/kg group compared to placebo in the mITT population for the CGI-I. EOT measured at day 54. Posttreatment follow-up at day 66. Improvement is lower score. LSmeans. (C) Change from treatment baseline of the 200 mg/kg group compared to placebo in the mITT population for the RTT-DSC. EOT measured at day 54. Posttreatment follow-up at day 66. Improvement is a decrease in score. Exact median test. Treatment baseline = day 14. CGI-I = Clinical Global Impression Scale–Improvement; EOT = end of treatment; LSmean = least-squares mean; mITT = modified intention to treat; RSBQ = Rett Syndrome Behaviour Questionnaire; RTT-DSC = Rett syndrome–Clinician Domain Specific Concerns; VAS = Visual Analog Scale.
Figure 2 Core efficacy measures demonstrating improvement in the 200 mg/kg group compared to placebo (A) Change from treatment baseline of the 200 mg/kg group compared to placebo in the mITT population for the RSBQ total score. EOT measured at day 54. Posttreatment follow-up at day 66. Improvement is a decrease in score. LSmeans: placebo response included as covariate in the model. (B) Absolute values of the 200 mg/kg group compared to placebo in the mITT population for the CGI-I. EOT measured at day 54. Posttreatment follow-up at day 66. Improvement is lower score. LSmeans. (C) Change from treatment baseline of the 200 mg/kg group compared to placebo in the mITT population for the RTT-DSC. EOT measured at day 54. Posttreatment follow-up at day 66. Improvement is a decrease in score. Exact median test. Treatment baseline = day 14. CGI-I = Clinical Global Impression Scale–Improvement; EOT = end of treatment; LSmean = least-squares mean; mITT = modified intention to treat; RSBQ = Rett Syndrome Behaviour Questionnaire; RTT-DSC = Rett syndrome–Clinician Domain Specific Concerns; VAS = Visual Analog Scale.CC BY-NC-ND · PubMed Central
Figure 3 Relationship between change from treatment baseline in RBSQ, CGI-I, and RTT-DSC and trofinetide exposure Relationship between change from treatment baseline in RBSQ, CGI-I, and RTT-DSC and AUC0–12 at different visits and over the active treatment period. (A) Relationship between percentage change from treatment baseline in RSBQ-total score and AUC0–12 at day 28. (B) Relationship between percentage change from treatment baseline in RSBQ-total score and cumulative AUC during the active dosing period. (C) Relationship between CGI-I scores and AUC0–12 at day 28. (D) Relationship between CGI-I score and cumulative AUC during the active dosing period. (E) Relationship between percentage change from treatment baseline in RTT-DSC score and AUC0–12 at day 28. (F) Relationship between percentage change from treatment baseline in RTT-DSC score and cumulative AUC during the active dosing period. Visit 3 (day 14, end of placebo run-in), visit 4 (day 21), visit 5 (day 28), visit 6 (day 42), visit 7 (day 54, end of treatment), visit 8 (day 66, posttreatment). Solid lines are obtained by linear regression. Where applicable, placebo data (AUC = 0) from different visits are pooled together. AUC = area under the concentration vs time curve; CGI-I = Clinical Global Impression Scale–Improvement; RSBQ = Rett Syndrome Behaviour Questionnaire; RTT-DSC = Rett syndrome–Clinician Domain Specific Concerns.
Figure 3 Relationship between change from treatment baseline in RBSQ, CGI-I, and RTT-DSC and trofinetide exposure Relationship between change from treatment baseline in RBSQ, CGI-I, and RTT-DSC and AUC0–12 at different visits and over the active treatment period. (A) Relationship between percentage change from treatment baseline in RSBQ-total score and AUC0–12 at day 28. (B) Relationship between percentage change from treatment baseline in RSBQ-total score and cumulative AUC during the active dosing period. (C) Relationship between CGI-I scores and AUC0–12 at day 28. (D) Relationship between CGI-I score and cumulative AUC during the active dosing period. (E) Relationship between percentage change from treatment baseline in RTT-DSC score and AUC0–12 at day 28. (F) Relationship between percentage change from treatment baseline in RTT-DSC score and cumulative AUC during the active dosing period. Visit 3 (day 14, end of placebo run-in), visit 4 (day 21), visit 5 (day 28), visit 6 (day 42), visit 7 (day 54, end of treatment), visit 8 (day 66, posttreatment). Solid lines are obtained by linear regression. Where applicable, placebo data (AUC = 0) from different visits are pooled together. AUC = area under the concentration vs time curve; CGI-I = Clinical Global Impression Scale–Improvement; RSBQ = Rett Syndrome Behaviour Questionnaire; RTT-DSC = Rett syndrome–Clinician Domain Specific Concerns.CC BY-NC-ND · PubMed Central
Figure 4 Cohen d effect sizes for the RSBQ and RTT-DSC-VAS (200 mg/kg vs placebo at day 54) Cohen d effect sizes for the RSBQ (A) and RTT-DSC-VAS (B). Cohen d values are unadjusted, that is, do not incorporate covariate information from treatment baseline or placebo response. bid = twice a day; RSBQ = Rett Syndrome Behaviour Questionnaire; RTT-DSC = Rett syndrome–Clinician Domain Specific Concerns; VAS = Visual Analog Scale.
Figure 4 Cohen d effect sizes for the RSBQ and RTT-DSC-VAS (200 mg/kg vs placebo at day 54) Cohen d effect sizes for the RSBQ (A) and RTT-DSC-VAS (B). Cohen d values are unadjusted, that is, do not incorporate covariate information from treatment baseline or placebo response. bid = twice a day; RSBQ = Rett Syndrome Behaviour Questionnaire; RTT-DSC = Rett syndrome–Clinician Domain Specific Concerns; VAS = Visual Analog Scale.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Glaze, D. G., Neul, J. L., Kaufmann, W. E., Berry-Kravis, E., Condon, S., Stoms, G., Oosterholt, S., Della Pasqua, O., Glass, L., Jones, N. E., Percy, A. K., Rett 002 Study Group, Glaze, D. G., Neul, J. L., Kaufmann, W. E., Berry-Kravis, E., Condon, S., Stoms, G., Oosterholt, S., Pasqua, O. D., Glass, L., Jones, N. E., & Percy, A.
Affiliations
  • From the Department of Pediatrics and Neurology (D.G.G.), Baylor College of Medicine, Houston, TX; Department of Neurosciences (J.L.N.), University of California, San Diego; Greenwood Genetic Center (W.E.K.), Center for Translational Research, Greenwood, SC; Pediatrics, Neurological Sciences, and Biochemistry (E.B.K.), Rush University Medical Center, Chicago, IL;Vital Systems, Inc. (S.C., G.S.), Rolling Meadows, IL; Clinical Pharmacology & Therapeutics Group (S.O., O.D.P.), University College...
  • Rush University Medical Center (US)
ORCID
Della Pasqua, Oscar
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-04-16
Volume
92
Issue
16
Pages
e1912-e1925
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0000000000007316
PMC
PMC6550498
OpenAlex
W2922881551
Cited by
160
References
42
Citations by year
2026: 8 · 2025: 14 · 2024: 46 · 2023: 33 · 2022: 14 · 2021: 15 · 2020: 22 · 2019: 6
FWCI
8.59
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Neurology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083211)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
trofinetide, Rett syndrome, pediatric patients, safety and tolerability, pharmacokinetics, neurodevelopmental disorders, symptom improvement, Clinical Global Impression Scale, dose-response relationship
MeSH terms
Adolescent, Anti-Inflammatory Agents, Non-Steroidal, Child, Child, Preschool, Double-Blind Method, Female, Glutamates, Humans, Rett Syndrome, Treatment Outcome, Glutamic Acid

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